This invention relates to kits, methods and compositions containing catecholic butanes for the delivery of such to subjects for the treatment of malignant, premalignant and benign tumors. This invention also relates to methods of making the foregoing compositions. In such methods of treatment, one or more catecholic butanes are administered to subjects via routes of delivery other than direct injection into the affected tissue, and other than topical application onto the affected tissue. This invention further relates to compositions comprising one or more catecholic butanes that are formulated appropriately for such modes of delivery and treatment.
Catecholic butanes, including nordihydroguaiaretic acid (“NDGA”) and its derivatives, have been used for the inhibition of tumor growth in certain experimental animals. For example, Jordan et al. in U.S. Pat. No. 5,008,294 described the use of a single dose of NDGA on a mammary carcinoma MX-1 xenograft in athymic nude NCr mice. In one experiment, NDGA was injected into the tumor one day following subcutaneous implantation of a 14 mg fragment of the human mammary carcinoma in the axillary region of the mice. Jordan et al. further described topical application of NDGA after day 23 of implantation of human breast adenocarcinomas in athymic mice. Some evidence of inhibition of tumor growth was observed in those experiments, but it is unclear whether the antitumor effect was durable.
Huang et al. in U.S. Pat. No. 6,417,234 and U.S. Pat. No. 6,214,874 described intratumor injection of a NDGA derivative, designated tetra-O-methyl NDGA or M4N, and another NDGA derivative, designated G4N, separately or together into mice implanted with HPV-16 transformed immortal mouse epithelial cells (C3). Huang et al. also found some evidence of suppression of tumor growth by these NDGA derivatives. It is unknown whether compounds such as these NDGA derivatives can be safely administered to other animals such as humans.
Certain of the catecholic butanes, such as M4N, which is a NDGA derivative, are hydrophobic compounds found to be soluble in dimethyl sulfoxide (“DMSO”). When the composition of M4N in DMSO was injected into the tumor, the composition appeared to penetrate most but not all of the tumor tissues. A possible explanation may be that the hydrophobic nature of the compound limits its penetration. It would be desirable if a formulation can be found for safe systemic administration of these hydrophobic compounds so as to improve their efficacy, expand their utility and yet maintain their biological activities, such as anti-tumor activities. It would further be desirable if the catecholic butanes, including the NDGA Compounds, can be safely administered by routes of administration other than by direct injection into the affected tissues or by topical application.
Moreover, intratumor injection or direct injection of drugs into affected tissues may not be an ideal treatment regimen. Patients sometimes experience injection site discomfort. In addition, many tumors are not amenable to intratumor injection of a therapeutic, and many may not respond to topical application of a therapeutic. It would be desirable if a different route of administration of these catecholic butanes can be found that would be safe and appropriate for the disease or condition and yet maintain the biological activities of such compounds.
Additionally, it is not known whether the catecholic butanes, including NDGA and NDGA derivatives (collectively, the “NDGA Compounds”), or formulations containing them can differentially inhibit the growth or progression of tumor growth in humans without adversely affecting normal tissues. It would be desirable if the catecholic butanes, including the NDGA Compounds can be formulated and administered in such a way as to spare the normal tissues of any adverse effects.
Further, a majority of human malignant tumors are both local and systemic in nature in that the primary malignant tumors are produced locally whereas the secondary tumors, seeded from the primary, are spread systemically to other tissues, or arise de novo from tissues similar to the source of the primary. The most appropriate therapeutic options, therefore, include those that deliver effective medication to the primary source of malignancy as well as to the secondary sources. It would be desirable if an effective therapeutic can be formulated that can access both the primary and secondary sources of malignancies.
It would also be desirable if the NDGA derivatives can be formulated in a manner that would facilitate delivery to targeted tissues and maintenance of a certain range of dose level in the targeted tissues.